Diabetes Control Using Postprandial Feedback

ABSTRACT

Disclosed is a postprandial glucose-measuring device for preventing the development of or reversing T2D. Included are methods for using the device as well as better use for invasive and noninvasive glucose meters. Further disclosed are novel exercise-sensitizing compositions useful for managing blood glucose levels in Type-2 diabetics with minimal risk of hypoglycemia. The disclosed glucose meters allow a user to also measure exercise and meal size—all with relatively instant feedback—more effectively than having to track the complexity posed by labels, glycemic index and calories. Also disclosed is integration of glucose-measuring devices with smartphones and health monitoring technology to make possible safe and effective interpretation of postprandial glucose readings by a patient to control or reverse Type-2 diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.62/071,044, filed Sep. 11, 2014, the U.S. Provisional Application No.62/177,905, filed Mar. 26, 2015, and U.S. Provisional Application No.62/183,267, filed Jun. 23, 2015, and the U.S. patent application Ser.No. 14/852,455 filed on Sep. 11, 2015 the contents of which are herebyincorporated by reference.

BACKGROUND

Type-2 diabetes (“T2D”) is one of the most common chronic diseasesafflicting humans. The hallmark of T2D is abnormally elevated bloodglucose levels. Further, dyslipidemia is encountered in many T2Dpatients. Dyslipidemia typically manifests itself as elevated LowDensity Lipoprotein (LDL), depressed High Density Lipoprotein HDL levelsand elevated triglyceride levels. About 79 million Americans ages hadprediabetes, a predisposition to develop diabetes, about 1.9 millioncases of Americans ages were newly diagnosed with T2D adding to the 25.6million, or 11.3 percent, of Americans with T2D in the United Statesaccording to the U.S. Department of Health and Human Services'estimates. As T2D progresses the regulation of blood glucose levelsfalters to the point of requiring supplemental insulin. Sedentarylifestyles are believed to be responsible for the increase in T2D, but,on the other hand, the conventional wisdom holds that making lifestylechanges is impractical. Thus, T2D is one of the more pressing healthproblems treated imperfectly by medications.

As to consequences of T2D, PostPrandial HyperGlycemia (PPHG), but notFasting HyperGlycemia (FHG), appears to independently predict theoccurrence of cardiovascular disease (CVD) events. In addition sustainedabnormally high glucose levels (Hyperglycemia) are associated with thelong term increase in the risk of strokes, blindness, thickening of theskin, dry skin, infections, and the like. Thus, T2D negatively impactsboth mortality and quality of life.

Considerable effort has been expended in developing better medications.Most T2D patients are treated with a combination of medications withmost combinations exhibiting risk of hypoglycemia. The least risk ofhypoglycemia is with excretagogues and carbohydrate digestion/absorptioninhibitors—provided they are not combined with other medications. Themedications fall in many classes such as (i) secretagogues (e.g.,Sulfonylureas and Meglitinide), (ii) insulin sensitizers (also known asThiazolidinediones), (iii) gluconeogenesis inhibitors (Biguanides andDipetidyl peptidase-4 inhibitors), (iv) excretagogues (SGLT2inhibitors), and (v) carbohydrate digestion/absorption inhibitors (alphaglucosidase inhibitors). There are in development medications/devices tocontrol appetite by manipulating satiety etc. and surgical weight lossprocedures—that cure T2D in about half of the patients.

For drugs approved for treating T2D, the Food and Drug Administration(“FDA”) requires that their labels include language stating that themedication “is indicated as an adjunct to diet and exercise to improveglycemic control in adults with type 2 diabetes mellitus”. How this isto be implemented in practice is still an unsolved problem.

Most medication for treating T2D increase the risk of hypoglycemia. Forinstance, extra exercise, a smaller or missed meal, or an infection canreduce blood glucose levels dangerously when diabetes is controlledprimarily with medications. T2D patients may end up in the EmergencyRoom due to a minor infection—fighting which suddenly may have consumedplasma glucose with replenishment inhibited by their medicationsresulting in hypoglycemia and a visit to the Emergency Room. Althoughexercise is recommended, it is not advisable without close supervisionin T2D patients due to the risk of hypoglycemia. Effectively exercise iscontraindicated for T2D patients being treated with conventionalmedications—other than the new class of SGLT2 inhibitors. The lattercarry the increased risk of urinary infections and possible elevation ofcreatinine levels. Thus, for most medication combinations levelsphysicians choose some hyperglycemia to guard against hypoglycemia.

With the possible exception of the glucagon-like peptide 1 analogs andthe thiazolidinediones, which lose their effectiveness eventually aswell, other antidiabetic medications lose their effectiveness to controlhyperglycemia over time. Therefore, in view of the difficulty inachieving optimal glycemic control for T2D patients using currenttherapies, there is an unmet medical need for new antidiabetictreatments, particularly those that can reverse the irresistible diseaseprogression.

The HbA1c test provides an indication of the average blood glucoselevels over about three months to help evaluate the efficacy of a bloodglucose control regime. It has become the de facto standard fordiagnosis and evaluation of T2D treatments, but this has reduced theutility for T2D patients of sophisticated home glucose measuringinstruments other than for confirming the infrequent hypoglycemiaevents. Naturally, attempts at developing a commercially successful andmedically useful non-invasive blood glucose meter, i.e., requiring noskin punctures, have mostly failed because of their difficulty inreliably detecting hypoglycemia. Bodily fluids (such as saliva, sweat,urine, tears) have glucose at about one fiftieth or even less of that inblood/plasma. Thus, for non-invasive glucose meters the unmet challengehas been to accurately and reliably distinguish between about 70 mg/dL,which is the low end of the ‘normal’ blood glucose levels and about 60mg/dL, when hypoglycemia sets in and flag 50 mg/dL levels as dangerousdue to impairment of cognitive abilities.

U.S. Pat. No. 6,102,872 by Doneen et al. discloses a saliva basedglucose measuring instrument. The '872 patent discloses detection ofglucose levels in saliva when blood glucose levels were at about 100mg/dL. U.S. Pat. No. 8,898,069 by Hood et al. discloses additionalsalivary glucose detection embodiments using a device enclosed in theoral cavity. US Published Patent Application No. US 2014/0197042 A1 byZhang et al. discloses measurement of salivary glucose with a resolutionof about 0.5 mg/dL with a lower limit of detection at about 1.5 mg/dLcorresponding to blood/plasma levels of about 100 mg/dL. Saliva basedglucose detection is being developed and tested by QUICK LLC. Somenoninvasive meters also use combination of spectroscopic techniques,such as the GlucoTrack meter. These, naturally are very expensivecompared to the practice of almost giving away meters that usestrips—with the revenue from sales of strips providing the requiredreturn but need less consumables. With periodic HbA1c measurementsdramatically reducing the utility of regular glucose monitoring in T2Dpatients, in effect, glucose meters are primarily sustained by their useby diabetics, who do need insulin to control their glucose levels.

Unmet remains the medical need for new and, more importantly, effectiveantidiabetic treatments for T2D to reverse its irresistible progressionunder the current treatment strategies.

SUMMARY

We have discovered that many fat or fatty acid absorption inhibitingcompositions and compounds have an entirely unexpected benefit. Theyfacilitate the use of postprandial exercise as a tool to regulateblood/plasma glucose levels and to even reverse Type-2 Diabetes and makepossible the design and use of an entirely different instrument thatintegrates diet, exercise and glycemic control. These substances havenot been reported to synergize with exercise, despite their use forrelated applications, such as weight loss. Advantageously, this effectdoes not impair the natural mechanisms for glucose level regulation.Further, since the fat or fatty acid absorption inhibiting compositionsof interest are not absorbed by the body to any great extent when takenorally since they simply pass through the digestive track. As a result,they pose minimal risks of causing hypoglycemia—including due toexercise—that accompanies most medications for treating Type-2 diabetes.

The utility of this discovery is in making possible multipleapplications, some of which are described next. It, naturally, allowsintegration of exercise with treatment of Type-2 diabetes with reducedto no risk of hypoglycemia. Further, it allows reduction in doses ofconventional drugs used to treat Type-2 diabetes to make the treatmentregime safer. They also reduce the calories taken up and reduce thetriglycerides levels as well as cholesterol levels, thus reducing thedoes of hyperglycemia inducing agents such as statins to controlcholesterol and lipids.

The Exercise Sensitizers do not necessarily cause or require weight lossas a precondition for treating T2D. However, they are very compatiblewith weight loss—which is advantageous in the long run.

Further, there is synergy in combining the Exercise Sensitizers withexcreatagogues like SGLT2 inhibitors, which facilitate excretion ofglucose via kidneys by inhibiting reabsorption of glucose in the upperureter. This combination allows pancreatic cells to rapidly recover andmeasurably reverse T2D in as short a time period as three months.

Then, there is made possible an entirely different instrument, aPostprandial Feedback Meter, integrating diet, exercise and glycemiccontrol using glucose level measurements. Such an instrument can be usedto build better habits by helping meter meals and exercise for immediatefeedback. An immediate advantage is in not having to track thecomplexity posed by labels, glycemic index and calories in the effort toarrest and even reverse T2D. Further, since glucose levels are generallyhigh in the postprandial period, this makes possible safe use ofnoninvasive glucose detection since high accuracy at low glucose levelsis not needed.

Finally, integration of such an instrument with smartphones willactually allow a user to do something useful with measured glucoselevels—i.e., be able to continually evaluate improvements in glycemiccontrol and sufficiency of exercise. The traditional wisdom is thatglucose levels in the postprandial period are not useful orinterpretable. With Exercise Sensitizers in play, this wisdom is clearlywrong because such glucose levels show predictable and actionablechanges in response to postprandial exercise. This enables compliance bydeveloping and maintaining habits and lifestyles for effective bloodglucose management while overcoming psychological challenges incombatting Type-2 diabetes.

Thus, disclosed is a postprandial glucose-measuring device useful inpreventing the development of or reversing T2D. Included are methods forusing the device as well as better use for existing invasive andnoninvasive glucose meters. These methods allow drastic reduction oreven elimination of many of the oral medications typically used tocontrol T2D, which reduction translates into fewer side-effects. Furtherdisclosed are novel exercise-sensitizing compositions useful formanaging blood glucose levels in Type-2 diabetics with minimal risk ofhypoglycemia. A useful exercise-sensitizer composition includes one ormore of tetrahydrolipstatin (generic name, orlistat), cholestyramine,colestipol, colestimide, colesevelam, and sevelamer, among many fat orfatty acid absorption preventing compositions. Their effectivenessincreases markedly in combination with an SGLT2 inhibitor. SGLT2inhibitors, the systemically absorbed medication in a preferredtherapeutic embodiment, may be used to speed up reversal of T2D.

In this description invasive detection of glucose means detection ofglucose levels in blood or plasma obtained by pricking a subject with alancet point or use of a probe inserted by breaking the skin. On theother hand, noninvasive detection of glucose means detection of glucosein a biological fluid like saliva, sweat or tears, obtaining which doesnot require pricking or breaking the skin. The measurements may bespectrometric, for example, using electromagnetic, thermal/infra-red,and/or ultrasonic signals.

The method further comprises recommending moderate exercise after ameal. The method also may include using a chair or other furnituremodified to facilitate exercise in an office, while travelling, say onplanes, trains or even in an automobile. Exercising may be by way of apivotable arm rest, pedals, or a foot rest that also provides adjustableresistance to provide exercise. And, of course, an office chair may alsofunction as a recumbent bike.

These and other aspects are explained further later with the aid of theaccompanying figures, a brief description of which follows.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an illustrative prior art method for treating type-2diabetes.

FIG. 2 shows an illustrative method for selecting a subject forpostprandial exercise based treatment for Type 2 diabetes.

FIG. 3 shows an illustrative method for adjusting a meal size anddetermine Exercise Sensitizer based reduction in Traditional Medicationlevels.

FIG. 4 shows an illustrative method for noninvasive detection ofglucose.

FIG. 5 shows an illustrative noninvasive postprandial glucose leveldisplaying method such that they look different from invasively obtainedglucose levels.

FIG. 6 shows an exemplary consumable for hosting a sensor for detectingglucose/triglycerides/creatine/creatinine.

FIG. 7 shows an illustrative method and exemplary postprandial devicefor measuring glucose, creatine and creatinine levels to use creatine asan internal standard.

FIG. 8 shows a prior art habit loop showing the development of a cravingto execute a routine in response to encountering a cue in order toachieve a result.

FIG. 9 shows a method for reporting results and motivational statisticsto a user to establish desirable habits using a smartphone, smartphonerelated accessories and health monitoring technology.

FIG. 10 shows an illustrative method to inculcate habits to treat type 2diabetes in accordance with our methods.

DETAILED DESCRIPTION

Contrary to conventional wisdom the changing postprandial glucose levelsare a good guide for determining the timing and sufficiency ofpostprandial exercise to improve glycemic control in subjects at risk ofor suffering from T2D. We have made the surprising discovery that fatand fatty acid digestion/absorption inhibitors also act as ExerciseSensitizers in that they enable use of postprandial exercise to adjustglucose levels. Further this integration results in gradually drivingdown dyslipidemia in addition to improving glycemic control.

This discovery allows for many other applications that were simply notpractical under the prior art. The disclosed exercise-sensitizingcompositions are useful for managing blood glucose levels in Type-2diabetics with vastly reduced risk of hypoglycemia when exercising. Wealso propose a redesign for glucose-measuring devices for use astherapeutic devices for effecting lifestyle changes.

A very useful exercise-sensitizer is tetrahydrolipstatin (orlistat),alone or more preferably in combination with one or more ofcholestyramine, colestipol, colestimide, colesevelam, and sevelamer. Itis possible to use a pharmaceutically acceptable salt, hydrate,polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof withinthe scope of this disclosure. This exercise sensitizer combination maybe further combined with an SGLT inhibitor, such as one or more ofPhlorizin, Canagliflozin((2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol),Dapagliflozin((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol),Empagliflozin((2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol),Remogliflozin(5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl6-O-(ethoxycarbonyl)-β-D-glucopyranoside), Sergliflozin(2-(4-methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside),and Tofogliflozin((1S,3′R,4'S,5'S,6′R)-6-(4-Ethylbenzyl)-6-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triolhydrate (1:1)), and Sotagliflozin. For the SGLT inhibitors it isacceptable to use an alternative SGLT2 inhibitor or pharmaceuticallyacceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, orstereoisomer within the scope of this disclosure.

Looked at another way, the Exercise Sensitizer may be formulated as asupplement to an SGLT inhibitor. Advantageously, such a supplement maycomprise not just an Exercise Sensitizer component but also supplementalfat soluble vitamin and nutrients and a source of Calcium. We discoveredthat such a supplement comprising Vitamin A, Vitamin D, Vitamin E andCalcium—for instance in the form of Calcium Carbonate—is beneficial andsynergistic with Exercise Sensitizers, including when combined furtherwith SGLT2 inhibitors and moderate exercise to treat T2D.

Also disclosed is integration of a Postprandial Feedback Meter withsmartphones, accessories like watches, and health monitoring technologyby making interpretation of glucose readings meaningful and actionableby a patient to control or reverse Type-2 diabetes. This integrationalso furthers developing and maintaining better habits and lifestylesfor effective blood glucose management. Over time the disclosed methodsand compositions result in regression of Type-2 diabetes. Thisintegration of methods, devices, compositions, and fine adjustments bythe patient also addresses the physiological and psychologicalchallenges in combatting Type-2 diabetes. This is timely since theUnited States alone has experienced a 60% increase in T2D over the lasttwenty years, a figure that attests to the unmet nature of problemsposed by this chronic condition.

Definitions

Blood/Plasma is the compartment comprising red blood cells and othercells that are carried in plasma that circulates in the body. Glucoseconcentrations by portable glucose meters are typically reported asthose in plasma.

Excretagogues are medications that lead to excretion of excess bloodglucose—typically by way of urine—and are usually not Glucose AbsorptionInhibitors.

Exercise Sensitizer means a substance that when administered orally isnot absorbed by the body to any significant extent but reduces therequired intensity, to usually no more than moderate intensity, andduration, usually of ten minutes to an hour though with no real hardlimit, of postprandial exercise to reduce postprandial glucose levelsinto a target range. In effect, this property is a combination oflowering insulin resistance and improving glycemic control but withoutimpairing the natural mechanisms for glucose level regulation. Thedesirable range for postprandial glucose levels is the normal range forblood/plasma glucose of about 70 mg/dL to 100 mg/dL. Examples ofExercise Sensitizers include fat or fatty acid absorption preventingcandidates like Orlistat (also known astetrahydrolipstatin((S)—((S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl)2-formamido-4-methylpentanoate)), Cetilistat (also known as2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one), Lipstatin([(2S,4E,7E)-1-β-hexyl-4-oxo-oxetan-2-yl)trideca-4,7-dien-2-yl](2S)-2-formamido-3-methyl-pentanoate), PolyEthylene Glycol and its lipophilic derivatives, Cholestyramine,Colestipol, Colestimide, Colesevelam, and Sevelamer and pharmaceuticallyacceptable salts, hydrates, polymorphs, solvates, prodrugs, enantiomers,or stereoisomers thereof.

Gluconeogenesis Inhibitors are medications that inhibit gluconeogenesis,the generation of glucose by the liver.

Carbohydrate Digestion/Absorption Inhibitors are medications thatinhibit absorption of glucose, including for instance by interferingwith carbohydrate digestion.

Glycemic Control is the ability to control blood/plasma glucose levels,usually within normal ranges for blood/plasma glucose.

Habit Cue means a trigger for initiating a sequences of behaviors oractions—often subconsciously.

Habit Result/Reward means the end result of performing the HabitRoutine, absent which the Habit Routine is meaningless.

Habit Routine means the sequence of steps triggered upon encounteringHabit Cue.

Hyperglycemia means blood glucose levels about or above 120 mg/dLHypoglycemia means blood glucose levels about or below 60 mg/dL.

Instructing means promoting use or a method of use by way of productinserts, user manuals, or advertising, such as for a glucose meter or amedication for treating T2D.

Insulin Sensitizers are medications that increase sensitivity toinsulin. Examples are medications classified as thiazolidinediones.

Invasive Glucose Detection means the detection of glucose levels in abiological fluid or tissue obtained by a procedure that requires atleast breaking the skin.

Noninvasive Glucose Detection means detection of glucose withoutrequiring a puncture to draw a biological fluid or sample.

Postprandial Exercise means exercise undertaken after a meal.

Postprandial Monitoring Device measures glucose following a meal—usuallywithin about three hours following a meal. This time period can belonger in T2D patients since their glucose levels do not come down asfast as those for subjects with normal Glycemic Control.

Saliva means the secretion in the oral cavity by salivary glands. It isoften sampled with contamination with food particles if the mouth hasnot been thoroughly cleaned.

Secretagogues are medications that cause increased secretion of insulin.Examples are medications classified as sulfonyl ureas.

SGLT inhibitors mean compounds that effectively block Sodium-GlucoseTransport proteins. There are several types of SGLT inhibitors, with theprimary ones being SGLT1 and SGLT2. SGLT2 inhibitors are found mostly inthe urinary system, where they remove glucose from urine and pump itback into the body such that normal urine has almost no glucose.Examples are SGLT2 inhibitors like Canagliflozin that work by allowingglucose to be excreted in urine.

Target Range means the glucose level or range into which glucose levelsshould be reduced by a subject according to general recommendations or aspecific recommendation by a physician, but not including blood/plasmaglucose levels of less than about 70 mg/dL or higher than about 140mg/dL.

Traditional Medications means medications such as (i) secretagogues(e.g., Sulfonylureas and Meglitinide), (ii) insulin sensitizers (alsoknown as Thiazolidinediones), (iii) gluconeogenesis inhibitors(Biguanides and Dipetidyl peptidase-4 inhibitors) used to treat T2D thatare capable of driving the system into hypoglycemia.

ILLUSTRATIVE EMBODIMENTS

Here we first discuss the broad outlines of our approach followed by adiscussion of the Postprandial Feedback Meter designs, novelcompositions that synergize with the use of the device and the novelmethods disclosed for managing T2D. With these realistically reversal oravoidance of T2D can be reasonably be expected in a large number of atrisk subjects—such as those with newly diagnosed T2D or those at risk ofdeveloping T2D. Then we describe the a Postprandial Feedback Meterdesign and its details that address both safety and operational aspects.The novel compositions are addressed next with some discussion on thisnew category of medications defined by their ability to sensitize asubject to exercise—by making the glucose levels responsive to exerciseas well as making exercise less cumbersome with the aim to reduceglucose levels. Finally we discuss the method taken as a whole todescribe how and why it helps form useful habits and bring aboutlifestyle changes.

We also present results of a reversal of T2D over about three months ina subject using the described methods as proof of concept for ourapproach. It should be noted that while much of the principlessupporting this approach are included in the detailed description, thistheory is not intended to act as a limitation on the scope of theclaims.

Exemplary Example of Prior Art

FIG. 1 is an illustrative prior art method 100 for managing T2D. At step105 blood/plasma glucose is directly measured. Alternatively it may bemeasured indirectly using HbA1c or by detecting glucose in the urine, orbe inferred from excessive thirst and the like. In all cases ablood/plasma glucose test is usually administered at some point toinitiate treatment. If the blood/plasma glucose level is below about 70mg/dL at step 110, then, at step 115, likelihood of hypoglycemia isevaluated. Control passes to step 120, during which if blood/plasmaglucose level is below about 60 mg/dL then control passes to step 125,during which assistance is provided, for instance by administeringsugars or glucose. Control then passes to step 130, during whichmedications and other factors are reviewed and adjusted to avoid futureepisodes of hypoglycemia. On the other hand if glucose levels in step120 are not below about 60 mg/dL, then the patient has low blood glucosebut is able to take actions, such as eat or ingest sugars in step 135 tostave off possible hypoglycemia. Control passes to step 140 forevaluation if possible hypoglycemia is a repeat incident and the like.Control passes to step 130 for a review and adjustment of medications,which naturally leads back to the next blood glucose measurement in step105.

During step 110, if the glucose levels are higher than 70 mg/dL, controlpasses to step 150 for evaluation if it is higher than 140 mg/dL. If so,control passes to step 155 for evaluation if this is a repeated fastingglucose level. If the fasting glucose level has repeatedly been high, asdetermined in step 155, medications are adjusted in step 160 to bettercontrol glucose levels. This adjustment may include the use of insulinif oral or other medications fail. Eventually most medications fail asthe disease progresses and insulin is required to control T2D in manypatients. Control then passes to step 145 to keep monitoring the patientand the disease progression with control passing to step 105. If at step150, glucose levels are below 140 mg/dL or at step 155 the high glucoselevel is an outlier, then control goes to step 145 for continuedmonitoring of the patient and disease and control returns to step 105.

Not all deviations of blood glucose levels have similar effects and somedeviations are more concerning than others. PostPrandial HyperGlycemia(PPHG), but not Fasting HyperGlycemia (FHG), appears to predict theoccurrence of cardiovascular disease (CVD) events. In addition sustainedabnormally high glucose levels are associated with the risk of strokes,blindness, thickening of the skin, dry skin, infections, and the like.But in the short term, too low a blood glucose level, termedhypoglycemia, is life threatening. As a result, in treating diabetes ifblood glucose levels are controlled using Traditional Medications to bevery close to the normal levels, the risk of hypoglycemia and of PPHGspikes increases as does overall mortality. Therefore, physicians err onthe side of allowing hyperglycemia rather than hypoglycemia whenprescribing medications. Unsurprisingly, sustained hyperglycemia makesT2D a progressive disease that is effectively impossible to reverse bymedications alone.

It is known that increased body weight and obesity are risk factors fordeveloping T2D. While targeting obesity may be sufficient for treatingT2D, we realized that it is not a necessary condition or even a usefultarget in and of itself. We have therefore treated weight loss as adistinct problem that is related to that of improving glycemic control.Thus, while both weight loss and improved glycemic control may beachievable in many subjects, weight loss is not required for betterglycemic control or even for reversing T2D. The primary focus should beon improving glycemic control.

A desirable T2D treatment program preferably should (i) minimize therisk of hypoglycemia; facilitate exercising; (ii) reduce thepostprandial glucose and/or triglyceride spikes; (iii) be easy toimplement; (iv) reduce sustained hyperglycemia by enabling close tonormal regulation of blood/plasma glucose; (v) provide cues and resultsto establish habitual compliance; and (vi) reverse or at least stop theprogression of or towards T2D.

Hypoglycemia is the major risk facing T2D patients using medications tocontrol their plasma glucose levels. Most of the medications fortreating T2D—including the standard of care treatment of initiatingtreatment with metformin (a biguanide)—carry a significant risk offacilitating hypoglycemia. An increase in glucose usage can result inhypoglycemia in T2D patients, which can quickly escalate to confusion,coma, and cognitive decline, and if not treated immediately, it can evenresult in death. For instance, in seven cases investigated by the Foodand Drug Administration (FDA), in hospital settings patients, most ofthem diabetic, were dosed with a maltose containing fluid which shows upas misleadingly elevated glucose readings in portable glucose readersusing the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)methodology. As a result they were treated with insulin forhyperglycemia, which instead resulted in causing hypoglycemia andseveral deaths as insulin increased the utilization of glucosedramatically.

The other challenge in treating T2D is in improving compliance sinceglucose spikes are not sensed by the patient. As a result there is notrigger for doing something to combat rising or high glucose levels.Further, as soon as patients feel even slightly well, many stop even thetask of regularly taking their medications leave alone exercisingregularly. Many approaches to correct this have been tried. Some testedapproaches include reminders for exercise, keeping logs of meals andfood intake, entering blood glucose readings in a database to allowcalculation of effectiveness of the medications and lifestyle factors intreating T2D etc. Smartphones have been pressed into service but havebeen in disfavor for continuous monitoring of glucose levels due toconcerns that it is impractical for such programs to meaningfullyinterpret the data and would more likely confuse the patients who mayunknowingly expose themselves to serious harm. The Diabetes Control andComplications Trial showed that reducing hyperglycemia was beneficial incombatting diabetic retinopathy but subsequent trial showed that tightglucose control with medications increased mortality. Thus, medicationsby themselves do not offer a viable treatment option.

Our method and Postprandial Feedback Meter overcome these limitationsbecause making measurements in the postprandial stage with postprandialexercise reduces the glucose levels rapidly. Further, the method makesit possible for a patient to make the fine adjustments in blood glucoselevels instead of relying on infrequent visits with a physician. Beingable to detect the need to exercise or when a meal was too large alsoprovides the cues and results needed for habit formation to improvecompliance. The patient can view the short term effects of post-prandialexercise and modify her or his lifestyle. The physician, in thisparadigm, tracks HbA1c levels and prescribes the proper use of thePostprandial Feedback Meter together with Exercise Sensitizer andpreferably an SGLT2 inhibitor at appropriate doses.

Further, Traditional Medications may be prescribed at lower and farsafer doses since they need not bring glucose levels close to normallevels. Instead with the methods disclosed herein the TraditionalMedications only need reduce blood glucose levels sufficiently to enablethe postprandial exercise in combination with an Exercise Sensitizer toprovide meaningful fine control.

Our methods also provide a practical context for implementingnoninvasive glucose monitoring. In the post meal context it ispreferable to use non-invasive glucose monitoring since there is noappreciable risk of hypoglycemia while the relaxation of the need toinvasively obtain blood makes compliance easier. Noninvasive measurementof blood glucose levels after a meal presents almost no risk of missinghypoglycemia because blood glucose levels are uniformly high and areexpected to be high. In our methods, these levels are reduced to adesired range only with effort in the form of exercise. In other words,this is when noninvasive detection of glucose is practical and useful.And then, the normal gluconeogenesis machinery steps in to preventhypoglycemia.

FIG. 8 illustrates a prior art habit loop. To inculcate a habit what isrequired is creating a craving for executing a set of steps upon beingpresented with a cue. The craving develops if the execution of the stepsproduces a desirable and immediate result. As an example, for brushingteeth, the Habit Cue is the morning breath and ablutions. In eachinstance, the steps of brushing include using toothpaste. But thetoothpaste in overwhelming instances is minted and provides the mintysensation as the desirable and immediate result of completing theexecution of the steps—the Habit Result/Reward. Failure to brush resultsin missing the expected minty feeling resulting in regular brushing moreoften than not by most. Thus, in a habit loop a Habit Cue is needed totrigger a set of steps, the Habit Routine, followed by a desirableresult, the Habit Result/Reward, making execution of the Habit Routineeffortless.

FIG. 2 shows an illustrative algorithm for deciding if standard of caretreatments for T2D is needed to manage blood sugar levels due topsychological or physical impairments that make postprandial exerciseimpractical. As shown in illustrative FIG. 2, the patient was capable ofengaging in exercise. FIG. 2 shows an exemplary algorithm for decidingif a patient can exercise safely. At step 200 the patient is evaluatedfor factors such as handicaps, CVD or emphysema and the like that wouldindicate that exercise would cause harm or is impractical. If thesubject is capable of exercising control goes to step 205, during whichthe fasting patient is administered an Exercise Sensitizer—with orwithout an SGLT2 inhibitor with a meal. For an adult, a dose may be, forinstance, about 60 mg. of orlistat as an Exercise Sensitizer. Controlthen flows to step 210, during which the meal portion size is evaluated.A possible standard may be that with fifteen minutes of exercise bloodglucose should drop to less than 100 mg/dL. If the blood glucose doesreduce in this manner, then a good therapy has been demonstrated and theroutine exits. However, if blood glucose level does not reduce to belowabout 100 mg/dL, then the meal size is adjusted down in step 215.Control then flows back to step 205 for the next dosing. On the otherhand, if the subject does have a reduction in blood glucose levels withpostprandial exercise, then control passes to step 220, during whichsubject's ability to comply is evaluated to ensure it is being tracked.Repeated failures would indicate that T2D should be managed withTraditional Medications as indicated in step 225. For reasonablycompliant subjects, then the subject is suitable to benefit frompostprandial exercise and Exercise Sensitizers to improve glycemiccontrol in step 230—including with the addition of an SGLT2 inhibitorand lipid soluble vitamins as well as calcium.

Example 1

A 54 year old man was diagnosed with Type 2 DM, dyslipidemia withoverweight (BMI 29). He was initially diagnosed to have prediabetes atage of about 35 and then at age=54 was noted to have overt type 2diabetes. At age 56 he was found to have HbA1c of about 8 with fastingglucose levels of 170 mg/dL. The family history was noteworthy with bothparents and sibling having diagnosis of hypertension, T2D and obesity.Physical exam noted BMI 30.2. He had received prescription for metforminand statin upon initial diagnosis to control glucose levels anddyslipidemia but had not continued the therapy in view of being advisedof the progressive nature of the disease and being discouraged by theprognosis and the failure to Metformin to sufficiently reduce the bloodglucose levels—even with the doubling of the Metformin dose.

Example 2

The patient of Example 1 was encouraged to track glucose levels,including postprandial glucose levels, to observe the effect ofpostprandial exercise and lifestyle changes. To control triglyceridemiahe also started over the counter orlistat at a 60 mg dose daily with adaily multi-vitamin supplement and an additional vitamin D supplement.He had discontinued metformin and statins. Instead close monitoring ofblood glucose levels was undertaken.

Postprandial exercise was initiated by the patient sua sponte after eachmeal as he sought to adjust the meals to control blood glucose levels.FIG. 3 shows how a hypothetical subject may adjust a diet using ourmethod to bring about lifestyle changes. At step 300 an evaluation ismade as to whether a subject's postprandial glucose level drops to about100 mg/dL or less using about fifteen minutes of exercise. If theglucose level does not drop to about 100 mg/dL, control flows to step305, during which one or more Exercise Sensitizers are administered.Control flows to step 310 during which an evaluation is made as towhether a subject's postprandial glucose level drops to about 100 mg/dLor less using about fifteen minutes of exercise. If this is ineffectivecontrol flows to step 315 during which the portion sizes are adjustedlower. Control then flows to step 320 during which the glycemic responseis evaluated for improvements. A failure to detect persistentimprovement leads back to step 305 for the next administration ofExercise Sensitizers—presumably the next day. On the other hand, if theglycemic response does improve then control flows to step 325 duringwhich Traditional Medications, if any, for treating T2D are evaluatedfor reduction. If no reduction is possible control because there are noTraditional Medications being administered then the control flows tostep 330 for management of blood glucose levels using postprandialexercise. If a reduction is possible then control flows to step 335 foreffecting a reduction or even elimination of the medications. Controlflows back to step 305 for the dosing next day. It should be noted thatat step 300 if the blood glucose level is below 100 mg/dL, control flowsto step 330 for continued management of blood glucose levels usingpostprandial exercise. This is useful for those with prediabetes sinceit ensures it is tracked early and corrected using the minimal treatmentdescribed herein.

Further, it should be noted that the time period of fifteen minutes isillustrative. It is possible to use a Postprandial Feedback Meter todecide when sufficient exercise has been undertaken based on the time atwhich glucose levels drop into the normal range or a specified rangelike at or below 100 mg/dL in this exemplary method. This makes themethod flexible and useful for physician treating patients so that theycan guide the patient with a demonstration of the actual effects ofportion control and exercise in as little as a single session of maybean hour. Of course, if more time is needed to arrive at the desiredadjustments allowed for by the illustrative exemplary method.

In Example 2, when using orlistat at 60 mg daily, the patient noticedthat blood glucose levels reduced to a level of about 90 to 100 mg/dL,which is in the normal range, after a modest meal with a brisk walkafter eating. The blood glucose levels stayed below 100 mg/dL forseveral hours. This shows the efficacy of Exercise Sensitizers inallowing a management of glucose levels using exercise instead of thestandard of care treatments for T2D in which exercise cannot and shouldnot be taken up willy-nilly due to the risk of hypoglycemia. Effectivelyexercise is contraindicated in standard of care treatments for T2D dueto the use of medications that can drive the glucose levels too low.

Example 3

The 56 year old subject of Example 2 exercised in the postprandial statewithin about an hour and a half after eating but was not treated withTraditional Medications or any Exercise Sensitizer for more than a week.Following exercise, blood/plasma glucose levels dropped by about 20mg/dL but further drops required intense exercise and the blood glucoselevels stayed stubbornly high.

The descriptions in the art are consistent with this observation in thatexercise required to reduce blood glucose levels is relatively intense.It is against this background that the role of Exercise Sensitizers inmaking even a brisk walk sufficient for reducing blood glucose levelsbecomes even more significant. As shown in Examples 10, 11 and 12, thelevel of exercise is relatively low intensity and does not take moretime than what has been observed for intense exercise in the prior artusing folks in prime physical shape.

Example 4

A 56 year old subject with T2D with fasting glucose levels of over 140mg/dL was treated with 60 mg Orlistat. The subject undertook exercise ina postprandial state within about an hour and a half after eating.Blood/plasma glucose levels dropped sharply to the normal range.Subsequently the blood/plasma glucose levels rose but stabilized for thenext several hours at about 95 to 110 mg/dL, well below the high levelsuntil the next meal indicating hysteresis in blood glucose levels whenadjusted with postprandial exercise.

Example 5

A 56 year old subject with T2D with starting fasting glucose level ofabout 140 mg/dL to 160 mg/dL and HbA1c of about 8 was treated withOrlistat. In one aspect, the 56 year old subject with T2D was treatedwith 60 mg Orlistat and exercised in a fasting state. Presumably asgluconeogenesis kicked in, the blood/plasma glucose level increased orremained steady in the high range over fifteen to thirty minutes insteadof the usual decline observed with postprandial exercise. Thus, the useof Orlistat did not prevent the rise in blood glucose levels but in thepostprandial state it allows a reduction in glucose levels usingexercise or other means for reducing glucose levels. Although notintending to be bound by theory, one factor may be the naturalinhibition of gluconeogenesis in the postprandial state. In addition,the release of fatty acids or lack thereof may affect the release ofcholecystokinin and other downstream effects and thus account for thesynergy between the postprandial state and the Exercise Sensitizers.

This result also shows that the risk of hypoglycemia is very low in thisregime since gluconeogenesis is not impaired.

Example 6

Over three months to speed up the slow progress the 56 year old subjectwith T2D with fasting glucose level of about 140 mg/dL and HbA1c ofabout 7.5 or above was treated with Orlistat at the lowest marketed doseof 60 mg and the lowest dose for either Canafliglozin (100 mg) andDapagliflozin (5 mg). Postprandial exercise with orlistat reducedtriglycerides to about 260 mg/dL from over 500 mg/dL.

An invasive glucose testing meter was used to simulate a post-prandialinvasive/noninvasive glucose monitoring device. Specifically acombination of orlistat and a SGLT2 inhibitor (Canafliglozin andDapagliflozin) was administered. Treatment with orlistat (60 mg) dailyalone with some.

The fasting glucose levels changed and continued to decrease overallover the three months. In combination with postprandial exercise theblood glucose levels dropped to high 70s or low 80s (in mg/dL) and thenslowly recovered over hours to less than about 100 mg/dL. Over threemonths the glycemic response improved and eventually reduced the fastingglucose levels to about 95 mg/dL (with some values as low as about 85mg/dL and no higher than about 100 mg/dL) and the HbA1c to about 6.2 atthe end of three months and 6.3 at the end of four months (oneadditional month).

The results show the surprising result that Type 2 diabetes can bereversed by our methods and compositions relatively easily—an entirelyunexpected finding considering the data and experience to date ofJanssen (See, JNJ-28431754 (Canagliflozin) NDA 204042 dated Jan. 10,2013 and titled Canagliflozin as an Adjunctive Treatment to Diet andExercise Alone or Co-administered with Other Antihyperglycemic Agents toImprove Glycemic Control in Adults with Type 2 Diabetes Mellitus). Thisinvestigation includes stratification of subjects by HbA1c. The data onpage 55 show that for starting HbA1c below 8 the observed improvementwas less than 0.8 even with 300 mg/day of Canagliflozin per day over aslong as 52 weeks. The usual improvement in HbA1c values expected withSGLT2 inhibitors is about 0.7 to 1.0. We observed improvements for thecombination of 100 mg/day of Canagliflozin with 60 mg/day of orlistatand postprandial exercise of about 1.3 in HbA1c as well as reduction infasting glucose levels to normal ranges in this short time period. It isreasonably expected that these efforts will lead to further reductionsin HbA1c with time—our observations covered three months for thisexperiment while other studies have been over almost a year but haveless favorable outcomes, which is evidence of synergy in ourcompositions and methods.

The fasting glucose levels were obtained using a portable glucose meterwhile the fasting glucose (again to check the meter and strip accuracy)and HbA1c were determined using laboratory tests that included a lipidpanel. The subject did not use statins at any point in this treatmentbut did have nutritional supplements like daily vitamins and calcium.Also the subject could not be fully compliant—many meals were notfollowed by exercise. The treatment with Exercise Sensitizer and SGLT2inhibitor was adhered to strictly. Still, the triglyceride levelsdropped to 260 and eventually to about 220 from about 500. The BMI didnot change appreciably and stayed at about 30. Thus, the approachdescribed herein performs far better than standard of care byidentifying a true synergy that is not predictable from isolated piecesof data.

Example 7

Upon discontinuing all medications subsequent to managing the reductionof fasting glucose levels into the normal range, the fasting glucoselevel rose to about 105 mg/dL and then stabilized illustrating thereversal of T2D with the three month treatment with Orlistat and GLUT2inhibitor (Canafliglozin or Dapagliflozin).

Example 8

The 56 year old subject with T2D undertook postprandial exercise. NoExercise Sensitizer was administered though the glycemic response hadimproved due to prior use of the method and orlistat. A week was allowedto allow the body to settle down to the absence of Exercise Sensitizersand SGLT2 inhibitors. Over twenty minutes of postprandial exerciseglucose readings were taken every 5 minutes for fifteen minutes. Bloodglucose levels dropped from about 175 mg/dL to about 135 mg/dL in fiveminutes and then stabilized at about 115 at ten and fifteen minutes.

Example 9

The 56 year old subject with T2D was treated with Pioglitazone 15 mg andpostprandial exercise but no Exercise Sensitizer or SGLT2 inhibitor.Over twenty minutes of postprandial exercise glucose readings were takenevery 5 minutes for fifteen minutes. Blood glucose levels dropped fromabout 175 mg/dL in steps to about 103 mg/dL at about ten minutes andthen levelled off. Thus, pioglitazone seems to act like a weak ExerciseSensitizer at this low dose except that it is absorbed into the body andhas a significant risk of hypoglycemia associated with it. However, thedata here shows that preferred Exercise Sensitizers perform better andwith no risk of hypoglycemia since they are not even absorbed by thebody.

Example 10

The 56 year old subject with T2D was treated with Exercise SensitizerColestipol (1 gm dose) and postprandial exercise. Over twenty minutes ofpostprandial exercise glucose readings were taken every 5 minutes forfifteen minutes. Blood glucose levels dropped from about 175 mg/dL insteps to about 94 mg/dL in about fifteen minutes.

Example 11

The 56 year old subject with T2D was treated with Exercise SensitizerColestipol (1 gm) before each meal and with 60 mg. of ExerciseSensitizer Orlistat and 100 mg. of Canagliflozin daily. After a lowglycemic index breakfast of about 300 to 400 calorie low fat yoghurtbase sweetened with sucralose and with sliced almonds, raisins, andfruit, postprandial exercise was undertaken. Over twenty minutes ofpostprandial exercise on an elliptical trainer at a resistance settingof 6, glucose readings dropped to about 81 to 84 mg/dL.

Example 12

The 56 year old subject with T2D was treated with Exercise Sensitizercolestipol (1 gm) before each meal and with 60 mg. of ExerciseSensitizer Orlistat and 100 mg. of Canagliflozin daily. Colestipol (1gm) was taken before lunch and breakfast while Orlistate at 60 mg. wastaken with 100 mg. Canagliflozin before dinner. Supplemental vitaminsand calcium were taken in the morning.

After a low glycemic index breakfast of about 300 calorie low fatyoghurt base sweetened with sucralose and with sliced almonds, raisinsand fruit, postprandial exercise was undertaken to evaluate the effectof intensity and duration of the exercise.

A PRO-FORM 14.0 SE Space Saver elliptical machine was used with the rampset at 25 degrees and exercise undertaken for twenty minutes with rpmmaintained at about 60. Resistance was set at 5 on the machine. Bloodglucose dropped to the low eighties (81 to 84 mg/dL) in twenty minutesfor resistance settings of 5 and 4. Repeating the exercise withprogressively lower resistance levels to 3 showed a reduction in bloodglucose levels to low eighties (81 mg/dL) in fifteen minutes suggestingrapid stabilization of low glucose levels with limited postprandialexercise.

Example 13

A 56 year old subject with T2D was treated with Exercise SensitizerColestipol (1 gm) before each meal and with 60 mg. of ExerciseSensitizer Orlistat and 100 mg. of Canagliflozin daily. Colestipol (1gm) was taken before lunch and breakfast while Orlistate at 60 mg. wastaken with 100 mg. Canagliflozin before dinner. Supplemental vitaminsand calcium were taken in the morning.

After a low glycemic index breakfast of about 300 calorie low fatyoghurt base sweetened with sucralose and with sliced almonds, raisinsand a banana, postprandial exercise was undertaken to evaluate theeffect of intensity and duration of the exercise.

A PRO-FORM 14.0 SE Space Saver elliptical machine was used with the rampset at 25 degrees and exercise undertaken for twenty minutes with rpmmaintained at about 60. Resistance was set at 2. Blood glucose droppedto 90 mg/dL in twenty minutes (to 103 mg/dL in 10 minutes and 97 mg/dLin 15 minutes).

This Example shows that even a low resistance setting of 2 suffices tohelp bring about reductions in glucose levels when assisted by ExerciseSensitizers. Such rapid drop in blood glucose levels without invitinghypoglycemia shows that this approach is far safer for productivelycombining exercise with medications than has been the case withTraditional Medications.

Example 14

Exercise intensity was estimated by way of blood pressure and heart ratemeasurements using a portable Relicon wrist cuff monitor. The conditionsfor exercising were as in Example 13 on the PRO-FORM 14.0 SE Space Saverelliptical machine with the ramp set at 25 degrees and exerciseundertaken for twenty minutes with rpm maintained at about 60.Resistance was set at 2. Readings were taken at five minute intervals.The procedure by CDC for measurements is to stop the exercise whilemeasuring the heart rate. That rate was measured at 96 bpm within 30seconds of pausing. The readings are as in the Table.

The Recommended Highest Heart Rate=208−0.7*58=167 or even 220−age=162.

At 96 bpm, the measurement taken using the CDC regime of pausing (for nomore than a few seconds needed to make the measurement) while measuringthe heart rate the regime corresponds to 96/167=57% or 96/162=59%. Bothare well below the cutoff of 70% to be considered high intensityexercise.

Another way of calculating exercise intensity uses the RecommendedHighest Heart Rate-Resting Heart Rate to get a reserve heart rate. Inthis measure, the Recommended Highest Heart Rate of 167 leads to areserve of 108 and the Recommended Highest Heart Rate of 162 correspondsto a reserve of 103. Then (96−59)/108=34% and (96−59)/103=36% of theheart rate reserve being used by exercise. It should be noted that thisintensity of exercise is far below what is recommended for managing T2Dby reducing weight.

All numbers are rounded or truncated.

Systolic Diastolic Heart Rate Notes Resting Prone 107 65 59  5 minutes124 70 84 While pedaling 10 minutes 134 76 117 While pedaling 15 minutes114 67 96 Paused pedaling CDC procedure 20 minutes 135 81 119 Whilepedaling

Example 15

Exercise intensity was estimated by way of blood pressure and heart ratemeasurements using a portable Relicon wrist cuff monitor. The conditionsfor exercising were as in Example 11 on the PRO-FORM 14.0 SE Space Saverelliptical machine with the ramp set at 25 degrees and exerciseundertaken for twenty minutes with rpm maintained at about 60.Resistance was set at 6. Readings were taken at five minute intervals.The procedure by CDC for measurements is to stop the exercise whilemeasuring the heart rate. The heart rates measured were at about 96 bpmwithin 30 seconds of pausing. The readings are as in the Table below.

Systolic Diastolic Heart Rate Notes Resting Prone 110 67 59  5 minutes118 65 89 Paused pedaling CDC procedure 10 minutes 106 67 96 Pausedpedaling CDC procedure 15 minutes 110 60 96 Paused pedaling CDCprocedure 20 minutes 106 58 100 Paused pedaling CDC procedure

The heart rate of about 95 (average of those at 5 min., 10 min., 15min., and 20 min. time points) achieved in this regime corresponds to95/167=57% of the Recommended Highest Heart Rate. Using the olderformula the numbers work out to be 95/162=58%. Both are well within the50% to 70% range for moderate intensity exercise. All numbers arerounded or truncated.

Example 16

A 57 year old subject with T2D was treated with Exercise SensitizerWelchol (625 mg) in the morning and evening before breakfast and dinnerrespectively. Supplemental vitamins and calcium were taken in themorning. Fasting blood glucose level was 102 mg/dL. After a about 400 to500 calorie breakfast of yoghurt sweetened with sucralose accompaniedwith a handful of almonds and peanuts with some rice flakes,postprandial exercise was undertaken to evaluate the effect of intensityand duration of the exercise. The conditions for exercising were as inExample 11 on the PRO-FORM 14.0 SE Space Saver elliptical machine withthe ramp set at 25 degrees with rpm maintained at about 60. Resistancewas set at 6. Readings were taken at ten minutes, next five minutes,next five minutes, next ten minutes, next ten minutes, next ten minutes,next ten minutes and another ten minutes time points. The readings bloodglucose at each of the resulting time points of 0 minutes, 10 minutes,15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutesand 1 hour, 10 minutes were found to be 124 mg/dL, 98 mg/dL, 102 mg/dL,98 mg/dL, 95 mg/dL, 96 mg/dL, 84 mg/dL, 100 mg/dL, and 97 mg/dLrespectively. The 84 mg/dL was confirmed with a fresh strip from anotherbatch within seconds and found to be 88 mg/dL, which suggests that itindicates a minimum after which gluconeogenesis resulted in an increasein blood glucose levels.

After cessation of exercise on the elliptical machine of about 1 hour,10 minutes, blood glucose was tracked about every hour to estimate thetime course of change in blood glucose levels between meals. At abouttwo hours and ten minutes after starting the exercise (about one hourafter ending the exercise), blood glucose level was determined to be 115mg/dL with about 16 oz. of diet Pepsi being ingested. At about threehours and ten minutes after starting the exercise (about two hours afterending the exercise), blood glucose level had reduced back to 100 mg/dLwithout requiring exercise, suggesting that the diet soda resulted insome limited gluconeogenesis, possibly due to stimulants like caffeinein it or due to other ingredients. At four hours and thirty minutesafter starting the exercise (about three hours and thirty minutes afterending the exercise), blood glucose level was determined to be 98 mg/dL.

Compatibility with Weight Management and HbA1c Reduction

Further treatment would likely reduce HbA1c numbers further as the postmeals glucose levels are reduced and compliance improves.Notwithstanding the long list of failures in treating T2D, aspects likesmartphone implementations are being explored. Several companies haveindependently taken up the task of creating noninvasive detection ofglucose. Google has been disclosed efforts in developing a contact lenswith blood glucose measuring capabilities. Even if an effort atdeveloping a contact lens succeeds, the device would have the samechallenge as current manufacturers of portable home glucose meters andstrips, viz., there is no use for the devices in the largest group ofdiabetics—the T2D patients and prediabetics. This is because other thanflag hypoglycemia, the glucose strip does not guide treatment decisions.

In our methods outlined here, it is possible to instruct a physician ora patient to use a Postprandial Feedback Meter in the postprandial stateto track the reduction in glucose levels—such as was done for Examples12 and 13. A noninvasive Postprandial Feedback Meter would be evenbetter since it would entirely take away the discomfort of a prick todraw blood. Quick LLC is developing one such meter based on saliva whileGlucoTrack is made by an Israeli company that uses Ultrasound,Electromagnetic and other radiations to track glucose in a meter thatrequires fewer consumables. Sanofi also has a strip that can detectglucose in the skin and communicate the values wirelessly—in the mannerenvisaged by sensors built into lenses and saliva based testing. All ofthese devices would benefit from our method and vice versa since theywill make it possible for a user to not only evaluate their mealsize—this approach is better than the ‘soda tax’ or ban beingexperimented with—but also engage in enough exercise to avoid the harmflowing from high blood glucose levels.

Exemplary Embodiments

Described next are more practical exemplary glucose measuring devicesfor the postprandial context to facilitate the implementation of ourmethod. It is noteworthy that presently the utility of portable glucosemeters is in question and their use is falling since they fail todeliver a clear medical benefit. As is seen from the example above andthe following description and discussion, appropriately designedPostprandial Feedback Meters and consumables are sorely needed forreversing or arresting the progression of T2D. Such exemplary glucosemeasuring devices for postprandial use have the capability for bothinvasive and noninvasive glucose detection.

Exemplary Glucose Measuring Device

Our preferred exemplary Postprandial Feedback Meter uses a bodily fluidlike saliva to noninvasively monitor glucose levels while it alsoincludes the ability of using blood/plasma for getting more accurateresults as well as calibrating the noninvasive testing against the moreaccurate values obtained using invasive glucose detection.Alternatively, it is possible to use spectrometric methods to estimateglucose levels in saliva or even through the skin. It should be notedthat similar results may be obtained using conventional invasive glucosetesting devices. If using electrochemistry then the reactions for salivaare similar to that with whole blood or plasma samples in that glucoseoxidase is used to generate Hydrogen Peroxide:

glucose+GOx(ox)→gluconic acid+GOx(red)  (1)

GOx(red)+2M(ox)→4 GOx(ox)+2M(red)+2H+  (2)

2M(red)→2M(ox)+2e−  (3)

Here GOx(ox) is glucose oxidase in its oxidized state. GOx(red) refersto the reduced state of the enzyme. M stands for metal (of an electrode)while M(ox) refers to a metal oxide.

Most portable (or home use) glucose meters uses a tiny finger prick todraw about 0.3 ml or even less of blood, which is applied to disposablestrips with two or three electrodes or groups of electrodes: (i) theworking electrode—which has the glucose oxidase or glucose dehydrogenaseenzymes, glucose hexokinase, any required molecules like flavin adeninedinucleotide glucose dehydrogenase with required buffers and cofactorsassociated with it to generate a glucose sensitive signal; (ii) thecounter electrode to complete the circuit with the working electrode andcarry most of the current; and (iii) a reference electrode, which isused as a voltage reference and is perturbed as little as possible byensuring little current is drawn from it. Glucose Oxidase is thepreferred enzyme because it is specific for glucose and generates asensitive signal reflecting the level of glucose with little effect dueto the presence of sugars like maltose.

One may need four to six measurements a day—each corresponding to aprick on a finger—which makes the current devices impractical forsustained use. Including noninvasive glucose detection would make suchglucose testing practical. While GlucoTrack is expensive upfront it doesnot require fresh strips for each measurement, combining it withinvasive testing is preferable.

For using saliva it is an additional complication that not only is therelittle glucose in saliva—about one fiftieth of that in blood/plasma, butthat glucose is continually absorbed from the oral cavity due to thepresence of glucose transporters, including SGLT1 type transporters, aswell as the enzyme amylase, which generates glucose—both processescompromise the stability and accuracy of inferring plasma glucose levelsfrom salivary glucose.

A commercially viable purely noninvasive portable glucose measuringdevice remains impractical since one of the requirements is that eachnew generation of portable glucose measuring devices be at least asaccurate as the preceding ones.

Further, in an aspect, to induce salivation to get fresh saliva samplesmore representative of plasma/blood glucose, we propose not only rinsingthe mouth but to use inhibitors of glucose transporters SGLT1, SGLT2 ina lozenge or another device to induce fresh saliva. Thus, containinglozenge comprising α-methyl-D-Glycoside or Phlorizin, both beinginhibitor/substrate of SGLT1 and/or SGLT2, nonsugar and noninterferingsugar substitutes, such as xylitol, to induce saliva and inhibitors ofα-amylase, such as maltohexaose and maltododecacose attached to theC-4-OH of acarbose (G6-Aca & G12-Aca) will both prevent generation ofglucose in the oral cavity and prevent update of glucose from the oralcavity. A preferred SGLT1/SGLT2 inhibitor is Phlorizin, a compoundisolated from nature (a flower for instance) and which started thesearch for a better compound. Phlorizin has activities against bothSGLT1 and SGLT2 but is too unstable to make it past the stomach. Thus,it is desirable to prevent uptake of glucose from saliva to give astable representation of glucose levels reflecting those inplasma/blood. Further, a mouth rinsing preparation that also includesinhibitors of SGLT1 is useful. Reducing sodium levels would also helpreduce SGLT1 activity in the oral cavity. Another alternative is, forinstance, Sotagliflozin (an inhibitor of SGLT1 and SGLT2), which may becombined with others like Dapagliflozin, Empagliflozin, or Canagliflozin(each an inhibitor of mostly SGLT2—they are selected to for as littlecross activity as possible against SGLT1) provides for furtherinhibition of glucose uptake from saliva while also promoting excretionof glucose. Such a lozenge and treatment of a subject improves thestability of glucose levels in the saliva and insures that they moreclosely reflect those in blood/plasma.

Thus, a saliva inducer that also spikes saliva withPhlorizin/Sotagliflozin and inhibitors of amylase is desirable to allowfor reliable and sensitive glucose detection. Whether such a spike isprovided by way of a lozenge, paste—for instance for use in a toothbrushlike device described in U.S. Pat. No. 6,623,698, or lyophilizeddeposits, it is useful to prepare saliva properly. FIG. 6 shows someaspects of a saliva testing consumable 600. Consumable 600 has areceiving trough 605 in which saliva can be spit out. Trough 605 mayadvantageously include lyophilized deposits of inhibitors of amylase tostabilize saliva. Trough 605 rests on a fluid impermeable bed 610 with abacking 615. Trough 605 is fluidly coupled to a filter 620 to keep outparticulates and bubbles. Area 625, coupled to filter 620 allows salivato flow by sensor 630 using capillary action. Fluidly connected block635 acts as a sink for the saliva. Preferably block 635 can be replacedif it gets too saturated to pull saliva from trough 605. While theelectrical contacts are not shown in this illustration, theelectrochemistry is well known. In some embodiments, the electrodesadvantageously include sensors for detecting Triglycerides, which ispresent in amounts reflecting, but at much lower absolute levels, thelevel in plasma/blood in saliva. To this end, the electrodes have alipase to break down fats into glycerol and fatty acids. Then, glyceroloxidase generates hydrogen peroxide to provide an estimate of changes intriglyceride levels in saliva. Since hydrogen peroxide is generated, itis also possible to integrate detection of glucose with that oftriglycerides on the same working electrode by adding glucose oxidase toprovide a signal reflecting the value corresponding to a preceding mealsince glucose is also detected by way of generation of hydrogenperoxide. This integration for detecting them in saliva is also possiblein an invasive test using blood. In both cases, longer integrationperiods lead to a better signal.

The current and anticipated regulatory requirements address the riskposed by the failure to detect hypoglycemia and failure to detectextreme hyperglycemia. The rational is that in such situations theclinical decision would likely be affected by the meter results—forinstance in a failure to timely ingest glucose. As a result close to thelower end of normal glucose levels, 75 mg/dL 99% of portable metersought to provide reproducible readings, which means within 15% of themeasured value—stricter than the requirement for being within 20% of themeasured value. Further, 99% of the meters should satisfy thisperformance target.

At 75 mg/dL the best portable glucose meters on the market meet therequirement for being within 15% standard at 100%. If the repeatedreadings should not vary by more than 10%, then the best portable metersperform at 98% to 100%. With even stricter standards of repeatedreadings not varying by more than 5%, the best meters perform at about95% to 98% of the tested portable meters or readings but many portablemeter brands falter to numbers well below 50%. For the best portablemeters the 5% reproducibility standard at about 75 mg/dL glucose levelsgives an error of about 3.75 mg/dL or less. In practice the error seemsto be of the order of 1 mg/dL or slightly less on the best meters.

In a prospective instrument measuring glucose in saliva, the use of adifference amplifier increases the sensitivity and with the use ofcatalysts and suitable membranes the electrode is made very specific forglucose by screening out interferrants. Increasing detection times fromabout 5 seconds to about 2 minutes further improves the resolution ofthe noninvasive measurements to a fraction of a mg/dL. Combining thesewith spectrometric detection of glucose in saliva provides a robustmechanism to measure glucose levels.

In addition to the reproducibility standard, the accuracy of theportable meter—as measured against laboratory measurements varies sinceit depends on the stability of the calibration. Home use glucose metersencounter more variations in conditions from long term storage of stripsto contaminated blood samples or interfering agents in blood,hematocrit, temperature, or even inadvertent dilution due to wet hands.They generally are within 10% for the best portable glucose meters. Bestportable glucose meters measure glucose levels accurate to within about1 mg/dL compared to laboratory analyzers, which is sufficient to meetthe need to detect hypoglycemia or hyperglycemia upon retesting with aninvasive glucose measurement as is depicted in FIG. 4.

With both invasive and noninvasive capabilities built into the sameinstrument, as is the case with the Postprandial Feedback Meterdifficulties in detecting and flagging hypoglycemia are overcome. Thisis illustrated in FIG. 4. During step 400 a meal is ingested. Next,during step 405 postprandial exercise is undertaken, during which orbetter following which in step 410 glucose levels are detectednoninvasively. If the glucose level is detected to be in the ‘Low’ rangein step 415, then the meter flags the readings as requiring invasivetesting in step 420. Invasive testing can be done on the same instrumentusing blood/plasma instead of saliva. Control flows from step 420 to 425for determining if the subject is hypoglycemic. If hypoglycemic,treatment is offered in step 430. Else the routine exits.

Presently the glucose readings are not considered useful if obtainedafter a meal or during or immediately after exercise because they changerapidly. We have discovered that this is actually the best time periodto determine glucose levels in a T2D patient since this is when thedefective glycemic response results in persistently high glucose levelsin the patient. Lowering them using postprandial exercise and ExerciseSensitizers and SGLT2 inhibitors helps control and reverse thedevelopment of T2D.

In one embodiment of the post-prandial monitoring device bothnoninvasive and invasive detection of glucose are possible. ThePostprandial Feedback Meter indicates invasive glucose detection withgreater accuracy than noninvasive glucose detection. Typically this isreported as a concentration in familiar units like mg/dL or mmol/liter.Further the noninvasive detection is readily distinguished from theinvasive detection of glucose as the latter is communicated by way ofbroad categories such as ‘low’, ‘normal’, ‘high’, which makes possibleuse of noninvasive glucose monitoring using a portable glucose measuringdevice. This is illustrated in the exemplary embodiment of FIG. 5.

Glucose is measured noninvasively in step 500. In step 505 it isdetermined if the glucose level is ‘High’. If not, control passes tostep 510 and an error is flagged because in the absence of high glucoselevels it is unlikely that measurements are starting in postprandialstate. Else control passes to step 515, during which a timer is startedto allow periodic glucose readings. Glucose readings are displayed as arange in step 520 to distinguish them from the more concentration unitsbased readings from standard more accurate invasive testing. In step525, glucose is measured noninvasively and again the displayed readingsare updated in a range based display in step 530. Step 535 allows fortesting if a preset time ‘T’ has passed. If yes, then anothernoninvasive test is made and control returns to step 525. Else, controlflows to step 540, during which is determined if the glucose level is‘high’. If not, the routine exits. Else control flows to step 535 toallow for ‘T’ time to pass prior to making another measurement.

To minimize the need for invasive glucose detection, e.g., by pricking afinger, an exemplary Postprandial Feedback Meter accepts a disposablenoninvasive detection strip with electrodes or an electrode arrangementsuitable for analyzing a biological fluid selected from the groupconsisting of saliva, tears and/or sweat to allow for non-invasivemonitoring. Such strips are typically manufactured by depositing theelectrodes and connectors on a support with membranes, and, if needed,filters added. In a preferred embodiment a plurality of electrodes isdisposed below a membrane such that there is at least one noisemeasuring electrode for measuring the background and a glucose electrodeassociated with an enzymatic portion to provide a signal responsive toglucose levels.

Typically when measuring glucose in blood/plasma, the reaction leads toa current when using glucose oxidase, thus making an amperometricdetection. A voltage is applied by the meter and the electrode currentis read as a measure of glucose. This works well when glucose levels arehigh and most glucose meters on the market use a similar approach. Withlow levels of glucose or with very small samples of blood/plasma it ispreferable to use background cancellation and other techniques to reducethe background to detect a very small signal. Further, instead of a veryquick detection—current portable meters detect glucose levels in about 5seconds—detection over more time allows integration of more data pointsand improves sensitivity. As a result, the postprandial noninvasivetesting need not detect and report the first glucose levels in 5 secondsbut could take one or more of the time periods from the group consistingof about 10 seconds, about 15 seconds, about 20 seconds, about 25seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45seconds, about 50 seconds, about 55 seconds, and about 60 seconds ormore but less than about 2 minutes. Preferably it further continuesupdating the glucose values as fresh sample of noninvasively obtainedbiological fluid is applied to provide continuous detection.

In a preferred embodiment use is made of the ability to detectcreatinine and creatine in saliva using electrochemistry. By way ofexplanation, detection of creatinine is customary for evaluating kidneyfunction. Creatinine is ordinarily in equilibrium with creatine in thebody and elevated creatinine levels indicate kidney malfunction since itis a waste product that is eliminated by the kidney. Healthy folks havecreatinine levels at less than about 1 mg/dL although muscular men mayhave as much as 1.3 mg/dL. Higher levels are flagged as requiringattention. Although other enzyme choices are possible, one set from U.S.Pat. No. 6,861,232 is as follows:

creatinine+H2O+creatininase→creatine  (4)

creatine+H2O+creatinase→sarcosine+urea  (5)

sarcosine+O2+H2O+sarcosine oxidase→glycine+formaldehyde+H₂O₂  (6)

As is readily seen in the above equations, the end product detected isH₂O₂. Thus, it is possible to detect just creatine using the formulationof equations 5 and 6. Or total level of creatine and creatinine may bedetected by adding the enzyme creatinase to further add the signal dueto creatinine from equation 4. While creatinine is a waste product andcan build up in blood/plasma, creatine is required by muscles and othercells for their functioning. It is made in the liver, kidney and thepancreas and transported to other tissues like muscles via blood. It istaken up from blood using active Sodium driven transporters. The levelin blood for creatine rarely goes up since it is taken up aggressivelyin a manner similar to that of glucose removal from urine and mostsecreted biological fluids. The level of creatine in blood is relativelysteady as it is pumped out until equilibrium is reached at a level ofabout 20 to 60 micrograms/dL and does not change appreciably over a fewminutes of exercise. This is true for creatinine as well. Thus, itbecomes to provide an internal standard in saliva, which has about oneseventh the level of creatine and creatinine as serum/plasma, using thecreatine level at the beginning of a measurement. Then creatinine isalso measured in units of initial creatine and so can glucose bemeasured. With no more than a scaling factor to relate comparableconcentrations of creatine and glucose, it is possible to better flagglucose levels at low glucose concentrations—that is after a few minuteof exercise when glucose levels would fall. For individuals onTraditional Medications as well as Exercise Sensitizers hypoglycemiaremains a concern. The use of creatine levels as an internal standardprovides a ready measure for dangerously low glucose levels even in aglucose poor fluid like saliva. FIG. 7 provides an illustration of sucha Postprandial Feedback Meter although many variations are possible. Itgoes without saying that folks taking creatin supplements or withdisorders in creatin transporters will not be proper candidates for sucha procedure and instrument.

In step 700 both glucose and creatinine and creatin are detected. Thenglucose level is checked in step 705 against a threshold derived fromthe creatin level. These compounds provide a ready measure of plasmaderived fluids and of an analyte from plasma that is generally held in anarrow range without being subject to pumps like the SGLT pumps. Glucoseranges are displayed in step 710 unless the glucose levels are not highenough to warrant being in a postprandial state. Control passes to step715, during which a timer is started to allow periodicglucose/creatine/creatinine readings. Glucose levels, and optionallycreatin/creatinine levels, are measured in step 720. In step 725,glucose levels are displayed after updating as a range. Step 730 allowsfor testing if a preset time ‘T’ has passed. If yes, then anothernoninvasive test is made and control returns to step 710 for resettingthe timer. Else, control flows to step 735, during which is determinedif measurements are complete. If so, the routine exits. Else controlflows to step 730 to allow for ‘T’ time to pass prior to making anothermeasurement.

However, reliability and accuracy of noninvasively detected glucoselevels to estimate blood/plasma glucose levels is often insufficient toallow reliably distinguishing between normal (about 70 mg/dL glucose)and hypoglycemia (about 60 mg/dL glucose) since in correspondingnoninvasively obtained fluids the resolution has to be good enough todistinguish between 1.4 mg/dL and 1.2 mg/dL, which is beyond the rangeof current portable glucose meters. Therefore, when glucose levels arelow, the Postprandial Feedback Meter is used to detect glucose inblood/plasma to verify the results from noninvasive glucose testing andact to correct hypoglycemia if detected. Further, in the postprandialcontext it is easier to detect most glucose levels since they arealready elevated.

In an embodiment the same exemplary strip can be used to detect glucoseinvasively or noninvasively. In this embodiment the signal level isdramatically lower when using saliva, tears and/or sweat compared tothat in blood/plasma, which can be used to identify if the biologicalfluid is blood/plasma or sweat/tears/saliva. The Postprandial FeedbackMeter detects may automatically decide that the biological fluid isblood/plasma or one of sweat, tears or saliva. Further, the user canconfirm the determination by the device or the absense of hemoglobin canbe used to confirm the absence of blood/plasma on the strip when lowlevels of glucose are detected.

The Postprandial Feedback Meter has an electrically conductive slot toreceive a disposable invasive/noninvasive strip for analyzing blood orplasma. It decides if the fluid is blood/plasma by one or more of (i)recognizing the range of the difference signal for blood being many foldgreater than from tears, sweat, or saliva, (for instance a glucose levelof about or less than 20 mg/dL (at levels of 50 mg/dL a person iscognitively impaired) is presumed to be noninvasively obtained while anoninvasive detection of about 6 mg/dL corresponds to about 200 mg/dLlevel in blood/plasma) or, alternatively, (ii) recognizing thedisposable invasive/noninvasive strip as being suitable for analyzingblood by its shape or an indicator included in the disposableinvasive/noninvasive strip. This indicator may be the presencehemoglobin or any other blood component level. Then both the absence ofhemoglobin and the lower signal level would indicate noninvasivemonitoring.

Hypoglycemia Detection in Noninvasive Glucose Detection

One of the major concerns in using glucose meters is the risk of afailure to timely detect hypoglycemia. Erroneous indication ofhyperglycemia or hypoglycemia or a failure to accurately detecthypoglycemia and the like are all reasons for a glucose meter to befound unacceptable. At the lower end, normal glucose levels in plasmaare at about 70 mg/dL and 60 mg/dL for hypoglycemia with 50 mg/dLindicating severe hypoglycemia, which at one fiftieth of thisblood/plasma concentration are noninvasively detected in saliva as 1.4mg/dL, 1.2 mg/dL, and 1 mg/dL respectively. At a detection limit of 0.5mg/dL it is possible to distinguish between 1.3 mg/dL and 1.8 mg/dL.Thus, in saliva a glucose level of about 1.8 mg/dL is in the normalrange while 2.3 mg/dL is near the upper end of the normal range while ator above about 2.8 mg/dL is hyperglycemia. The closer the glucose levelsget to about 1.3 mg/dL in saliva, the greater the possibility of missedhypoglycemia. The latter possibility is addressed in our method byfollow up invasive testing to ensure the actual blood/plasma level isnot too low compared to about 70 mg/dL, the lower limit for normalglucose levels. Thus, noninvasive testing for glucose possible with aPostprandial Feedback Meter device to help determine if postprandialexercise is adequate without a significant risk of missing hypoglycemiain rare instances. It should be noted that the risk of hypoglycemia islow in the postprandial time period anyway and the risk is even lower ifTraditional Medications are not used as was the case in the describedillustrative examples. Thus, an acceptable glucose meter has todistinguish between glucose at about 70 mg/dL and 60 mg/dL and not failto detect glucose at 50 mg/dL or lower. The exemplary PostprandialFeedback Meter meets this requirement because current invasiveblood/plasma analyzing devices already satisfy this requirement.

In the exemplary description above, a noninvasive glucose detectiondevice with a limit of 1 mg/dL can detect normal ranges at levels ofabout 2.3 mg/dL as in saliva as postprandial glucose levels fall to thislevel with exercise. If the levels fall below about 2 mg/dL, follow upnoninvasive testing may be used to ensure the absence of hypoglycemia.By using creatine levels as an internal standard allows another measureto flag possible hypoglycemia even early and reliably.

The use of a glucose detection device having both invasive andnoninvasive detection allows invasive detection of glucose levels whenthe noninvasive detection indicates even the possibility of hypoglycemiato allow timely intervention. Further the use of categories fornoninvasive glucose level reporting readily allows recognition ofnoninvasive readings from invasively obtained glucose levels when usedin a post-prandial setting, as is the case for a Postprandial FeedbackMeter, the risk of encountering hypoglycemia is remote since thesubjects have just been subjected to a glucose level spike due to thepreceding meal.

The Postprandial Feedback Meter has a display that indicates sufficiencyof exercise for glycemic control if it detects glucose level fallingbelow a threshold, or a reduction by a prescribed percent of a peakblood glucose level, or being within a prescribed range for the blood orplasma glucose level, or the blood/plasma glucose level being less thanabout 110 mg/dL, more preferably being less than about 100 mg/dL, andmost more preferably being less than about 90 mg/dL.

Such a drop tells the user that the post-prandial exercise can bestopped although there is no requirement to cease exercisingimmediately. In one embodiment, the Postprandial Feedback Meter displayindicates the glucose level as one of the group consisting of ‘Low’,‘Desired’, ‘Moderately High’, ‘Excellent’, and ‘Too High’ categories,wherein for blood/plasma the low′ category encompasses a range of belowabout 75 mg/dL, the ‘Desired’ category encompasses a range from about 70mg/dL to about 130 mg/dL, more preferably from about 70 mg/dL to about120 mg/dL, and most preferably from about 70 mg/dL to about 100 mg/dL,the ‘Moderately High’ category encompasses a range from about 130 mg/dLto about 180 mg/dL, the ‘Excellent’ category encompasses glucose levelsof about 70 mg/dL to about 80 mg/dL and the ‘Too High’ categorycorresponds to glucose levels of about 180 mg/dL or higher.Corresponding categories for noninvasive glucose detection can bespecified taking into account the limit of glucose detection. In anaspect, some of the categories may overlap and even multiple categoriesmay be displayed to a user to provide a sense of changes in glucoselevels as they go down with postprandial execise.

Alternative categories may be implemented to reflect the limitations inestimating blood/plasma glucose levels from those detectednoninvasively. Thus, in view of the lower glucose levels in such fluids,only three categories could be implemented, such as ‘Low’, ‘Acceptable’and ‘High’, with the low′ category reading requiring invasive retestingto address the possibility of hypoglycemia.

In another aspect, an exemplary Postprandial Feedback Meter includes anantenna for communicating over a wireless connection to a smartphone ora smartphone affiliated device or a health or fitness device.

The Postprandial Feedback Meter admits of some novel exemplaryconsumables. In particular, there is the strip that can be used tomeasure glucose in blood/plasma as well as saliva/sweat/tears etc. Inaddition, a lozenge compatible with the strip is preferably used tocause salivation while also inhibiting salivary amylase and SGLT1. Thisenables reliable detection of glucose levels in the saliva whenmeasuring glucose levels.

Exemplary Compositions

While some patients may not need the Exercise Sensitizer, its useensures predictable glucose level reductions in response topost-meal/postprandial exercise. With the use of an Exercise Sensitizerthe size of the meal need not be impractically small. We determinedOrlistat, a pancreatic lipase inhibitor, which inhibits the absorptionof fats in the gut among its other effects, as a particularly effectiveExercise Sensitizer at even low doses. A low dose of Orlistat makes asubject sensitive to exercise induced blood glucose level reductionafter a meal although by itself. Orlistat is ineffective in changingglucose levels and may even result in an increase in glucose levels whenexercise is undertaken in a fasting state even after ingesting Orlistat.Advantageously Orlistat is not absorbed by the body and is excreted out.Thus, most of its direct effect is on the molecules in the digestivetrack. It further reduces or even eliminates spikes in bloodtriglyceride levels after a meal.

The size and nature of the meal is forgiving if together with Orlistatis administered a glucose transporter inhibitor. We used inhibitors ofGLUT2, which also help reduce the spikes in glucose levels by helpingexcrete excess glucose in urine as it is absorbed into the blood/plasmacompartment. Further glucose excretion is aided by using betterformulated beverages to facilitate excretion of excess glucose withoutgetting electrolytes out of balance. Better design of furniture andfixtures for aiding in such exercise allows the patient to exerciseuntil the blood glucose levels have reached the desired range.

In another aspect, we have discovered that some compositions are usefulfor making T2D patients' glucose levels more exercise sensitive. Thus,sensitized, a short spell of moderate exercise is sufficient to lowerblood glucose levels in as little as five or ten minutes. Combining suchsensitization with a glucose excretagogue allows for a very tolerablelifestyle modification routine that does not require tiny meals,unforgiving compliance, or uncomfortably strict dietary controls. Anexample Exercise Sensitizer composition for controlling blood glucosecomprises an effective amount of a lipase inhibitor; an effective amountof a glucose excretagogue to stimulate excretion of blood glucose toreduce the level of blood glucose level; supplemental nutrients andpharmaceutically acceptable vehicles or excipients. Several examples ofeach of these types of substances are well-known,

Thus, for instance in an exemplary composition tetrahydrolipstatin iscombined with a glucose excretagogue selected from the group consistingof Canagliflozin((2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol),Dapagliflozin((2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol),Empagliflozin ((2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol),Remogliflozin(5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl6-O-(ethoxycarbonyl)-β-D-glucopyranoside), Sergliflozin(2-(4-methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside),and Tofogliflozin((1S,3′R,4'S,5'S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triolhydrate (1:1)), and Sotagliflozin (an inhibitor of both SGLT1 and SGLT2Sodium Glucose Transport protein types 1 and 2) or a pharmaceuticallyacceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, orstereoisomer thereof. A preferred composition includes as a glucoseexcretagogue Dapagliflozin, Sotagliflozin, Empagliflozin, orCanagliflozin. A more preferred excretagogue is Canagliflozin. An evenmore preferred excretagogue is Sotagliflozin since it potentiallyimproves glucose detection using saliva by inhibiting SGLT1. Othercomponents preferably included in the exemplary compositions includecholestyramine and colestipol and supplemental nutrients, whichinclusion improves the efficacy of the composition.

Of these exemplary compositions we have tested combinations of 60 mg ofOrlistat with either 5 mg of Dapagliflozin or 100 mg of Canagliflozin.We have also tested a combination of Colestipol with Orlistat and anSGLT2 inhibitor. Although both combinations performed well, thecombination of Colestipol with supplemental nutrients in the morning andthe combination of Orlistat and the SGLT2 inhibitor at dinner time arepreferable. This routine could be implemented with a blister pack withmorning and evening pills that make the task almost error free.

The advantage of the exemplary compositions is that in the trialscorresponding compositions sped up the process of recovery from T2D. TheExerciser Sensitizers are not absorbed by the digestive system. Indeed,adding a bile salt sequestrant selected from the group consisting ofcholestyramine, colestipol, colestimide, colesevelam, sevelamer,DEAE-cellulose, β-cyclodextrin, γ-cyclodextrin, guanidinoethylcellulose,and DEAE-Sephadex, with Colestipol the preferred tested component, tothe composition improves the performance and ease of use with minimalrisk of hypoglycemia. In this strategy fine control over glucose levelsis by way of exercise and under control of the user. Preferred bile acidsequestrants are cholestyramine and colestipol.

The major benefit provided by the preferred compositions is that theyleave the normal gluconeogenesis mechanism unmolested, thus drasticallyreducing the risk of hypoglycemia while delivering regression of T2D.However, this benefit is reduced if it is necessary to use additionalmedications in patients with more difficult to treat T2D. Suchmedications (such as insulin secretegogues like sulfonylureas, insulinsensitizers and gluconeogenesis inhibitors like metformin and the like)likely would be needed at lower doses in most instances, which wouldfurther reduce the risk of hypoglycemia but not to the extent possiblein the absence of such additional medications. These lower doses foreach of the medications have not been determined yet but can be readilydetermined with routine experimentation.

Weight Loss

A frequent desirable result is weight loss—which is distinct fromimproved glycemic response and regulation. However, weight loss often issufficient for improving glycemic response even if it is not alwaysnecessary—although it is a far more difficult a target than improvingglycemic response. In subjects also desiring weight loss, it is a simplematter to extend on or more of the postprandial exercises to furtherweight loss. The biggest factor for bringing about weight loss is diet.This our system already modulates using the Postprandial Feedback Meterto control portion size. This disclosure is primarily concerned withimproving the glycemic response but is also useful in addressing therelated problem of weight loss.

Our Method Bringing Together Exercise Senzitizers and Habits forLifeStyle Changes

A treatment for a potentially chronic condition or one requiringtreatment over a long period needs to be habit forming in order to beeffective. To form a habit one needs at least a cue, a habit routineexecuted upon detecting the cue and a result—which should be desirableenough to pin down the habit and generate a craving to execute the habitupon encountering the cue—best done more of less subconsciously. Thus,the failure to execute a habit should nag at the subject. Further, FIG.8 outlines the Habit Lop 800 that can bring about lifestyle changesusing our methods. There is Habit Cue 805, which in our methods isimplemented preferably as the act of eating or observing thenoninvasively obtained glucose level getting higher. Habit Cue 805causes execution of the Habit Routine 805, which, in turn, results inshowing a drop in glucose levels to normal ranges which acts as theHabit Result/Reward 815. After obtaining the Habit Result/Reward thesystem is primed to sense the next Habit Cue 805 and repeat the HabitLoop 800.

An example of successful habit formation is provided by the adoption oftoothpaste for improving dental hygiene by way of regular brushing.Early toothpastes were about equally effective as to dental hygiene andmade similar claims. But regular brushing refused to take off. However,one brand suddenly changed this static state of affairs. PEPSODENT™marketed a toothpaste that promised an alluring smile—as did manyothers—but also provided a minty aftertaste as a result. The absence ofthe minty result caused its users to remember to brush and the mintytaste told them that brushing was done—it provided a stand—in for thedesired result of improved dental hygiene. Similarly, to help folksclimb out of a debt trap, Pay and Win′, an experimental program offeredby Lutheran Social Services in Duluth, Minn., offered a raffle drawingto folks overwhelmed by the debt and struggling to make even the minimummonthly payments. Those who steadily paid down their loans each monthbecame eligible for the raffle drawings each month. “When you know youhave a hope of winning,” says one of the participants, Mrs. Hanson,“what a motivation!” The impetus of a cue in the form of the need toenter the raffle (at no additional cost) to avoid the opportunity costhelped borrowers get their finances in order as well as feel lessoverwhelmed immediately, which provided a desired result for financialplanning. Upon winning the raffle, the learned healthier financial habitencouraged them to pay down the debt to further along the process ofself-discipline for better financial management. In treating T2D,lifestyle changes have not happened because the cues and the results arefar too distant from the desired behavior and the competing cues forinitiating alternative incompatible habits have immediate results in theform of enticing food or simply resting. Thus, providing suitable cuesand results for controlling T2D remains an unmet need.

We determined that it is possible for many T2D patients, and inparticular newly diagnosed or those at risk of developing T2D, to takecharge of their blood glucose levels safely and even reverse the diseasecourse by providing rapid feedback on the result of their actions. Thisfeedback is in the form of postprandial glucose levels that providesinformation on the effect of diet and/or exercise immediately followinga meal. FIG. 9 illustrates on such method using the smartphone platform.In step 900 anonymized information is sent to a central server. Duringstep 905 a comparable standards are received. Using the receivedstandards, a rank is calculated for the subject during step 910. Then topromote habits based on performance in a shared community, a rank andimprovement is displayed in step 915.

We discovered that exercising prior to a first meal/breakfast is mostlyineffective in substantially changing blood glucose levels in T2Dpatients although it may be effective for losing weight or buildingmuscle tone etc. As a result mere exercise does not provide immediatefeedback or benefit since weight loss is over months, if at all, and aT2D patient can notice few motivating changes flowing from exercising,which is harder due to insulin resistance.

Exercising after a meal, preferably about thirty minutes after a meal iseffective in reducing blood glucose levels and reduces blood glucoselevels into the normal range with an Exercise Sensitizer making apatient's plasma/blood glucose levels responsive to Post PrandialExercise (“PPE”).

An occasional failure for a rapid reduction in blood glucose levelsfollowing post prandial moderate exercise is due to excessive calorieintake. Thus, practicing the method with a small meal is sufficient todemonstrate the efficacy of the method to a patient. Then adjusting thesize of the meal is something the patient can do to make surepostprandial glucose levels can be reduced into the desired range.

Most easily digested carbohydrates are absorbed early. Without intendingto be bound by theory, we believe that a failure to reduce blood glucoselevels to a ‘normal’ range in about twenty to thirty minutes of exerciseindicates excessive caloric intake. As a result, getting a measure ofthe triglyceride levels is also useful to provide feedback to a subjectabout the quality and nature of the meal together with the result ofglucose level reduction by post-prandial exercise. Over time, bymodifying lifestyle with post-prandial exercise and better designedmeals the glycemic response improves and allows a subject to transitionfrom being classified as a T2D to being glucose intolerant and even freeof T2D. Such a routine is illustrated in FIG. 10.

The desired habit is of regular postprandial exercise to reduce bloodglucose levels to the normal range—even if it does not result in weightloss. The disclosed methods generate cues and desirable results usingglucose level measurements to indicate sufficient exercise and/ordesirable portion sizes. In a preferred embodiment, glucose levels aredetected after a meal and lowered using moderate exercise into adesirable range. Such a range may be prescribed by a physician. Thus,the cue is partaking of a meal with concomitant increase in glucoselevels. In response to detecting the increase in glucose levels thesteps to be executed include postprandial exercise. The reward orresults is by way of getting control over blood glucose levels bydriving them into a desirable range. The exercise is continued until theglucose levels reach the desired range or exercise has been undertakenfor a prescribed duration if the glucose levels do not reach the desiredrange. Thus Postprandial Feedback Meter operates well in the very zonedisfavored by experts for interpreting glucose levels for improvingglycemic control and minimizing postprandial glucose spikes. Over timethe glycemic response improves and medications are titrated down as T2Dreverses.

In an aspect, providing additional sinks for the excess glucose in theblood/plasma compartment further reduces the post meal spike in bloodglucose levels by way of glucose excretagogues. The compositionsdescribed herein include an Exercise Sensitizer agent, the preferredExercise Sensitizer agent being tetrahydrolipstatin (Orlistat), a waxysolid. This agent also reduces the postprandial triglyceride spikes andwhere intense exercise may be needed, using it (or another ExerciseSensitizer) allows for its substitution by a brisk walk.

Our method for improving glycemic control sticks because it is designedto establish habits. Habits are what humans exist by. Psychologists notethat habits account for forty percent (40%) or possibly much more of thedaily decisions. Once a habit is formed, it is effortless to execute anda failure to execute it nags instead. Here the failure to exercise nagsonce it is clear that it is within the patient's control to normalizethe glucose levels. On the other hand, success in reducing glucoselevels provides a sense of control.

In FIG. 10, during step 1005 a small meal is taken. The measurement ofglucose levels in step 1010 acts as a Habit Cue resulting in the HabitRoutine of moderate postprandial exercise in step 1015. If the glucoselevel is higher than 100 mg/dL during step 1020, exercise is continuedduring step 1025. If the exercise duration has been longer than, saythirty minutes, as determined in step 1030, control flows to step 1035during which either the meal size or the Traditional Medication dose orboth are adjusted. Else if the glucose level is determined to be lessthan about 90 mg/dL in step 1040, exercise can be terminated with asense of achievement of the Habit Reward/Result of controlling bloodglucose levels successfully. If the level is not at or below about 90mg/dL,

Exploiting the Hysteresis in Blood Glucose Levels

We discovered that upon reducing blood glucose levels using exercise,the blood/plasma glucose levels increased rather slowly after exerciseor even stayed steady. On the other hand, if blood/plasma glucose levelswere increased in T2D patient, they decayed slowly. Thus, the rapidreduction in blood/plasma glucose levels brings out a rapid reduction inHbA1c measures.

Synergy Between Post-Prandial Exercise and Medications

We discovered that medications like orlistat synergize with postprandialexercise unlike Traditional Medications that require close supervisionin view of heightened risk of harm. Blood glucose levels drop sharplywith exercise in an Exercise Sensitizer treated subject. Failure toengage in exercise results in minimal glycemic benefit while exercisewithout eating after taking orlistat also had minimal effects.

Providing for Non-Invasive Monitoring

Invasive glucose monitoring is a potentially big hurdle, except in thepostprandial context. It is preferable to design devices, such as aPostprandial Feedback Meter, to continuously or noninvasively detectblood glucose and triglycerides from saliva, sweat, and tears such thatthe limit of detection is about 0.5 mg/mL—which is technically practicaland useful.

Presently glucose levels detected using handheld or home glucose metersare not really useful for any immediate action to be taken by a patient.For instance, GlucoSuccess (Massachusetts General Hospital) for type 2diabetics and prediabetics allows for entry of finger-stick glucosereadings. But there is little to do with the readings other thanresearch.

Noninvasive monitoring in accordance with the disclosed methods has theadvantage of the natural integration of the data with a smartphone orother fitness focused electronic devices. Using a suitably anonymizeddata base of other users of such a device can provide a target ofmaintained glucose levels to each user to meet or exceed with eachsession of postprandial exercise. Such a target may be the best readingsobtained by a user matched for age and the like in a last month, or overthe course of a year or in a locality or zip code or even state orcountry etc. Even an average for such a grouping is a reasonable targetto meet. One such implementation is illustrated in FIG. 9. Thus, theblood/plasma glucose levels are naturally and immediately affected bythe actions taken by a user.

Advantageously, it is possible to include in the smartphone executableapplication a functionality for detecting a heart rate and blood flow.Preferably, the smartphone/health monitoring executable applicationcommunicates with a backend support facility to securely store patientdata using the cellular phone network while providing anonymized data inthe form of targets to motivate subjects and make postprandialexercising a competitive and pleasurable experience.

Throughout this application various publications/patents are referred toand the disclosures of these publications, all books and all patents andpatent application publications referred to herein are herebyincorporated by reference in their entirety into the subject applicationto more fully describe the art to which the subject invention pertains.

It is apparent that the above embodiments and description and directivesmay be altered in many ways without departing from the scope of theinvention. For example, many embodiments could use an appetitesuppressant to further weight loss or bring about a greater change thanwithout. Further, various aspects of a particular embodiment may containpatentable subject matter without regard to other aspects of the sameembodiment. Still further, various aspects of different embodiments canbe combined together. All references cited herein are incorporatedherein by reference for all purposes. Accordingly, the scope of theinvention should be interpreted in a manner consistent with theseprinciples and in light of the claims.

1-20. (canceled)
 21. A postprandial monitoring device for providingfeedback to a subject to assist in adjusting glucose levels by way ofpostprandial exercise, the device comprising: an enzyme selected from agroup consisting of glucose oxidase, glucose dehydrogenase, and glucosehexokinase for detecting a glucose level in a semi-invasively sampledbiological fluid; a display for showing the glucose level by way of aplurality of categories selected from a group consisting of a Lowcategory encompassing a range of below about 70 mg/dL, a Desiredcategory encompassing a range from about 70 mg/dL to about 130 mg/dL, orfrom about 70 mg/dL to about 120 mg/dL, or from about 70 mg/dL to about100 mg/dL, a ‘Moderately High’ category encompassing a range from about120 mg/dL to about 150 mg/dL, a ‘Excellent’ category encompassingglucose levels of about 70 mg/dL to about 85 mg/dL and the ‘Too High’category encompassing glucose levels of about 150 mg/dL or higher.
 22. Apostprandial monitoring device for providing feedback to a subject toassist in adjusting glucose levels by way of postprandial exercise, thedevice comprising: an enzyme selected from a group consisting of glucoseoxidase, glucose dehydrogenase, and glucose hexokinase for detecting aglucose level in a semi-invasively sampled biological fluid; a displayfor showing the glucose level by way of a plurality of categoriesselected from a group consisting of a category flagging need for moreaccurate testing of glucose levels encompassing a range of below about70 mg/dL, a Desired category encompassing a range from about 70 mg/dL toabout 130 mg/dL, or from about 70 mg/dL to about 120 mg/dL, or fromabout 70 mg/dL to about 100 mg/dL, a ‘Moderately High’ categoryencompassing a range from about 120 mg/dL to about 150 mg/dL, a‘Excellent’ category encompassing glucose levels of about 70 mg/dL toabout 85 mg/dL and the ‘Too High’ category encompassing glucose levelsof about 150 mg/dL or higher.
 23. The postprandial monitoring devicethat communicates a detected glucose level depending on a detectionmethod, wherein invasively or semi-invasively detected glucose levelsare communicated as concentrations and noninvasive glucose detection iscommunicated by way of overlapping categories selected from a groupconsisting of a Low category encompassing a range of below about 75mg/dL, a Desired category encompassing a range from about 70 mg/dL toabout 130 mg/dL, more preferably from about 70 mg/dL to about 120 mg/dL,and most preferably from about 70 mg/dL to about 100 mg/dL, a‘Moderately High’ category encompassing a range from about 120 mg/dL toabout 150 mg/dL, a ‘Excellent’ category encompassing glucose levels ofabout 70 mg/dL to about 85 mg/dL and the ‘Too High’ categoryencompassing glucose levels of about 150 mg/dL or higher.
 24. Thepostprandial monitoring device of claim 23, wherein the device can makeboth invasive and non-invasive measurements.
 25. The postprandialmonitoring device of claim 24 wherein the display when indicating the‘Low’ category also indicates an urgent need for checking glucose levelsusing invasive measurements using.
 26. The postprandial monitoringdevice of claim 24, wherein a noninvasive glucose test takes a timeperiod selected from a group consisting of about 10 seconds, about 15seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55seconds, and about 60 seconds or more but less than about 2 minutes. 27.The postprandial monitoring device of claim 24 for providing feedback toa subject to improve glycemic control, the device comprising: a singleuse consumable strip for measuring blood/plasma glucose level; and amulti-use consumable for non-invasive glucose level measurements. 28.The postprandial monitoring device of claim 24 providing feedback to asubject to improve glycemic control, the device comprising: a single useconsumable strip for measuring blood/plasma glucose level; and a singleuse consumable for non-invasive glucose level measurements using abiological fluid like saliva, or sweat.
 29. The postprandial monitoringdevice of claim 28 providing feedback to a subject to improve glycemiccontrol, the device further comprising: a display or transmissionfacility for reporting a function of the difference as a measure ofglucose levels; and wherein the display indicates noninvasive glucosedetection results as one of a plurality of categories instead ofconcentration units for glucose levels, and further flags glucose levelfalling below a threshold, or a reduction by a prescribed percent of apeak blood glucose level, or being within a category for the blood orplasma glucose level.
 30. The postprandial monitoring device of claim 31for providing feedback to a subject to improve glycemic control, whereinthe device communicates measurements to a smartphone.
 31. Thepostprandial monitoring device of claim 31 providing feedback to asubject to improve glycemic control, wherein the device operates with asmartphone as a system to transmit anonymized results and comparisonsand rankings with other comparable user's results on one or more of agroup consisting of meal size control, glycemic control, and weightloss.
 32. A kit comprising the postprandial monitoring device of claim28 providing feedback to a subject to improve glycemic control, the kitincluding a consumable saliva inducer to spike saliva with an effectiveamount of an amylase inhibitor and an effective amount of an SGLTinhibitor in the form of a pharmaceutically acceptable salt, hydrate,polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof.